(1S)-3-Methylamino-1-(2-thienyl)propan-1-ol (“Duloxetine alcohol”) is a building block in Duloxetine synthesis. Duloxetine® is a drug which is currently at the approval stage and is intended to be used in the depression and incontinence fields of indication.
EP-B-0273658 describes a process for preparing the base corresponding to Duloxetine by reacting 2-acetylthiophene with formaldehyde and dimethylamine in a Mannich reaction, reducing the keto group of the Mannich base thus obtained to give the racemic (S)-3-N,N-dimethylamino-1-(thien-2-yl)propan-1-ol, etherifying the alcohol function with naphthyl fluoride and finally converting the dimethylamino group to a methylamino function. The desired naphthyl ether enantiomer is obtained using chiral starting materials or by resolution of the racemates at the stage of the final product, for example via the salts using optically active acids or chromatography on a chiral stationary phase.
U.S. Pat. No. 5,362,886 describes an analogous process which comprises adding S-mandelic acid to the racemic propanol obtained after reduction of the keto group. The S-enantiomer of the alcohol, obtained in this process, is used in the subsequent reaction stages.
EP-A-0457559 likewise describes a process analogous to that of EP-B-0273658. Here, the keto group of the Mannich base is reduced to the S-enantiomer form of the alcohol by using the asymmetric reduction system LAH-Icb (lithium aluminum hydride [(2R,2S)-(−)-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol]). The disadvantage here, besides the costs, is the sensitivity of the LAH-Icb reduction system which is stable only for a few minutes.
W. J. Wheeler and F. Kuo describe in Journal of Labelled Compounds and Radiopharmaceuticals, volume XXXVI, No. 3, pages 213 to 223, a process for preparing Duloxetine. To this end, thiophene-2-carbonyl chloride is reacted, in a Stille coupling, with vinyl tri-n-butylstannane in the presence of catalytic amounts of benzylchloro-bis(triphenylphosphine)palladium(II) in DMPU (dimethylpropyleneurea) to give 1-(thien-2-yl)-propenone of the formula (V)
which is subsequently converted, by treatment with hydrogen chloride, into 3-chloro-1-(thien-2-yl)propan-1-one of the formula (VI)

The chloropropanone obtained in this way is then reduced using a chiral oxazaborylidine and BH3 to give (S)-3-chloro-1-(thien-2-yl)propan-1-ol of the formula (VII)

The alcohol obtained in this way is converted, by successively reacting with sodium iodide and subsequently with methylamine, into (S)-3-methylamino-1-(thien-2-yl)propan-1-ol. Subsequent successive reaction with sodium hydride, 1-fluoronaphthalene and hydrogen chloride produces Duloxetine in the form of the hydrochloride.

Hal=halogen
T. Stiliger et al., in Chemie Ingenieur Technik (74) pages 1035-1039, 2002, describe substrate-coupled cofactor-regenerating processes for the enzymic enantioselective reduction of ethyl 5-oxohexanoate to give ethyl (S)-5-hydroxyhexanoate.